Magnetic resonance imaging (MRI) is an appealing noninvasive approach for early cancer diagnostics and therapeutics. While the imaging capabilities of these instruments have revolutionized imaging technology, the resolution of the instrument is limited to the elucidations of lesions within the body on the order of 1 mm. This limitation of the instrument has led to the development of several types of contrast enhancement agents including magnetite/dextran-based nanoparticles and chelated gadolinium contrast agents, which are currently available on the market and used widely in clinical applications. However, gadolinium (Gd) complex contrast agents are effective only when present in millimolar concentrations. Because of the superparamagnetic property, iron oxide nanoparticles have been found effective in nanomolar concentrations and can better serve as contrast enhancement agents for MRI. Apart from serving as contrast enhancement agents, superparamagnetic nanoparticles can be used as drug carriers for controlled drug release; they can accumulate in tumors very efficiently through enhanced permeation and retention.
However, when nanoparticles are conjugated with target agents or undergo any surface modification, particle agglomeration as a result of their large surface-to-volume ratio becomes a primary concern. When nanoparticles agglomerate, they not only lose their intended functionality, but can also be quickly cleared by macrophages or accumulated in the reticule-endothelial system before they can reach the target cells.
One approach to solving this problem is to modify the particulate surface with poly(ethylene glycol) (PEG) self-assembled monolayers. Surfaces covered with PEG have proven to be nonimmunogenic, nonantigenic, and protein resistant. While the PEG moiety provides an efficient system to increase particulate circulation time in blood, the nanoparticle systems must also be coupled with tumor targeting agents to be useful for the intended applications. Thus, the PEG moiety immobilized on nanoparticles must also provide an active functional group capable of conjugating with targeting agents.
PEG is used widely to functionalize proteins and peptides for drug delivery. Research in cell targeting has also utilized functional PEG molecules conjugated with folic acid on liposomes. Monofunctional PEG molecules coupled to proteins are known to prolong the particle circulation time in blood and reduce immunogenicity. While functionalized carboxyl or amine PEGs are widely available, they remain expensive and require chemical modification to convert to their corresponding silanes. Further, these functional PEGs are available mainly in high molecular weights, which may inhibit PEG monolayer self-assembly on the nanoparticle surface due to the labile nature of PEG molecules. Currently available PEGs can conjugate with only one type of functional group present in targeting agents, typically either amine or carboxyl groups, and, in most of cases, they are not suitable for nanoscaled devices such as nanoparticle systems due to their high molecule weight. PEG silylation normally occur in organic solution, whereas conjugation with tumor targeting agents such as folic acid or antibodies needs to be conducted in aqueous solution. Thus, PEG self-assembled monolayers (SAM) must be flexible enough to prevent agglomeration during solvent exchange and remain active in solvents to provide a terminus for conjugation.
Despite the advances in the use of nanoparticles as contrast agents and drug carriers noted above, a need exists for nanoparticles that can be surface-modified to function as both contrast enhancement agents and drug carriers simultaneously, allowing real-time monitoring of tumor response to drug treatment. The present invention seeks to fulfill this need and provides further related advantages.